BCL6 is the most commonly involved oncogene in B-cell lymphomas, and is expressed constitutively in a majority of patients with two most frequent forms of lymphoma: the diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma (FL). Many of these BCL6 positive tumors require the continued presence of BCL6 in order to maintain their survival. BCL6 is a member of the BTB/POZ family of transcriptional repressors. BCL6 mediates its effects on gene silencing through recruitment of the SMRT, N-CoR and BCoR corepressor proteins. The BTB domain of BCL6 provides an extended groove like surface to which a linear peptide from the SMRT, N-CoR and BCoR corepressor can bind with high affinity. This protein-protein interaction is required for BCL6 to repress critical checkpoint regulatory genes such as ATR and TP53. We hypothesize that drugs designed to occlude the BCL6 BTB domain corepressor binding groove will block the ability of BCL6 to repress its critical target genes and force lymphoma cells to undergo cell death, which could be enhanced by targeting complementary biological pathways. Along these lines, we have developed a peptidomimetic inhibitor of BCL6 called RI-BPI (retro-inverso BCL6 peptidomimetic inhibitor) with favorable potency, pharmacokinetics, toxicity profile and efficacy. The proposal brings together collaborating scientists with expertise in peptidomimetic drug design, lymphoma biology, hematopathology and clinical research. They will leverage their combined experience in these different fields with the goals of 1) Developing chemical-mimetics of RI-BPI, 2) determining the mechanism and efficacy of cell killing of RI-BPI and derivatives alone and in combination in a spectrum of DLBCL cell lines in vitro and in vivo, 3) determining the response of primary DLBCLs to BPI ex vivo and identify biomarkers predictive of response to RI-BPI, and finally 4) to translate BCL6 targeted therapy to the clinic and determine the safety, activity, and optimal dosing of RI-BPI in patients with BCL-6-positive DLBCL. By the end of the funding period, we expect to be moving peptidomimetic BCL6 inhibitor drugs into phase II clinical trials.